Quantitative Genetics Validates Previous Genetic Variants and Identifies Novel Genetic Players Influencing Alzheimer’s Disease Cerebrospinal Fluid Biomarkers

Article type: Research Article

Authors: Ramos de Matos, Mafalda^{a; †} | Ferreira, Catarina^{a; †} | Herukka, Sanna-Kaisa^b | Soininen, Hilkka^b | Janeiro, André^a | Santana, Isabel^c | Baldeiras, Inês^c | Almeida, Maria Rosário^c | Lleó, Alberto^d | Dols-Icardo, Oriol^d | Alcolea, Daniel^d | Benussi, Luisa^e | Binetti, Giuliano^f | Paterlini, Anna^e | Ghidoni, Roberta^e | Nacmias, Benedetta^g | Meulenbroek, Olga^h | van Waalwijk van Doorn, Linda J.C.ⁱ | Kuiperi, H. Bea jⁱ | Hausner, Lucrezia^j | Waldemar, Gunhild^k | Simonsen, Anja Hviid^k | Tsolaki, Magda^l | Gkatzima, Olymbia^m | Resende de Oliveira, Catarina^c | Verbeek, Marcel M.ⁱ | Clarimon, Jordi^d | Hiltunen, Mikkoⁿ | de Mendonça, Alexandre^a | Martins, Madalena^{a; *}

Affiliations: [a] Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal | [b] Institute of Clinical Medicine - Neurology, University of Eastern Finland, and Department of Neurology, Kuopio University Hospital, Kuopio, Finland | [c] Neurochemistry Laboratory, CHUC - Centro Hospitalar e Universitário de Coimbra, Neurogenetics Laboratory, CNC - Center for Neuroscience and Cell Biology and CNC.IBILI, Faculty of Medicine, University of Coimbra, Portugal | [d] Department of Neurology and Sant Pau Biomedical Research Institute, Memory Unit, Hospital de la Santa Creu i Sant Pau, Autonomous University of Barcelona, Barcelona, Spain, and Centro de Investigación Biomédica en Red en enfermedades Neurodegenerativas, CIBERNED, Madrid, Spain | [e] Molecular Markers Laboratory, IRCCS Cento S. Giovanni di Dio Fatebenefratelli, Brescia, Italy | [f] Molecular Markers Laboratory and MAC Memory Clinic, IRCCS Cento S. Giovanni di Dio Fatebenefratelli, Brescia, Italy | [g] Department of Neuroscience, Psychology, Drug Research and Child Health, University of Florence, Florence, Italy | [h] Department of Geriatrics, Radboud University Medical Center, Donders institute for Brain, Cognition and Behaviour, Radboud Alzheimer Center, Nijmegen, The Netherlands | [i] Department of Neurology, Department of Laboratory Medicine, Radboud University Medical Centre, Donders institute for Brain, Cognition and Behaviour, Radboud Alzheimer Center, Nijmegen, The Netherlands | [j] Department Geriatric Psychiatry (CIMH), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany | [k] Department of Neurology, Danish Dementia Research Centre, Rigshospitalet, University of Copenhagen, Denmark | [l] 1st Department of Neurology, Aristotle University of Thessaloniki, Makedonia, Greece and Greek Alzheimer Association, Greece | [m] Greek Association of Alzheimer’s Disease and Related Disorders “Alzheimer Hellas”, Greece | [n] Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland

Correspondence: [*] Correspondence to: Madalena Martins, PhD, Instituto de Medicina Molecular João Lobo Antunes, Av. Professor Egas Moniz, Edifício Egas Moniz, P1C74, 1649-028 Lisboa, Portugal. Tel.: +35 1 217999411/Ext. 47149; Fax: +35 1 217999412; E-mail: [email protected]. and Instituto de Tecnologia Química e Biológica António Xavier, Universidade NOVA de Lisboa ITQB NOVA, Av. da República, 2780-157 Oeiras, Portugal. Tel.: +35 1 214469250; Fax: +35 1 214411277; E-mail: [email protected].

Note: [†] These authors contributed equally to this work.

Abstract: Cerebrospinal fluid (CSF) biomarkers have been extensively investigated in the Alzheimer’s disease (AD) field, and are now being applied in clinical practice. CSF amyloid-beta (Aβ1–42), total tau (t-tau), and phosphorylated tau (p-tau) reflect disease pathology, and may be used as quantitative traits for genetic analyses, fostering the identification of new genetic factors and the proposal of novel biological pathways of the disease. In patients, the concentration of CSF Aβ1–42 is decreased due to the accumulation of Aβ1–42 in amyloid plaques in the brain, while t-tau and p-tau levels are increased, indicating the extent of neuronal damage. To better understand the biological mechanisms underlying the regulation of AD biomarkers, and its relation to AD, we examined the association between 36 selected single nucleotide polymorphisms (SNPs) and AD biomarkers Aβ1-42, t-tau, and p-tau in CSF in a cohort of 672 samples (571 AD patients and 101 controls) collected within 10 European consortium centers. Our results highlighted five genes, APOE, LOC100129500, PVRL2, SNAR-I, and TOMM40, previously described as main players in the regulation of CSF biomarkers levels, further reinforcing a role for these in AD pathogenesis. Three new AD susceptibility loci, INPP5D, CD2AP, and CASS4, showed specific association with CSF tau biomarkers. The identification of genes that specifically influence tau biomarkers point out to mechanisms, independent of amyloid processing, but in turn related to tau biology that may open new venues to be explored for AD treatment.

Keywords: Alzheimer’s disease, cerebrospinal fluid biomarkers, endophenotypes, European multicenter study, quantitative trait loci

DOI: 10.3233/JAD-180512

Journal: Journal of Alzheimer's Disease, vol. 66, no. 2, pp. 639-652, 2018